Primary intraorbital inflammatory lumpy lesion: A rare case report

Rationale: Eosinophilic angiocentric fibrosis (EAF) is considered to be a kind of benign IgG4-related disease, and it is more often found in the nasal cavity. We present a pretty rare case of orbital EAF that is unlike any other reported case for this case is an IgG4 negative orbital EAF and successfully treated by the fronto orbitozygomatic approach surgery. Patient concerns: This is a 68-year-old man from a rural area of Inner Mongolia Autonomous Region, went to our hospital for a 2-month history of vision loss with a local hospital orbital computer tomography which showed that there was a lesion in his left orbit. The inspection of the patient revealed that the patient left eye was protruding outward and the left eyelid unable to complete open or close. And his left eyeball movement had difficulty in all directions. Postoperative pathology diagnosed that this was a case of IgG4-negative EAF case. Diagnoses: Orbital EAF. Interventions: Surgical radical resection and postoperative glucocorticoid therapy. Outcomes: After surgery, the left eye vision of this patient increased to 0.6 tested in the standard logarithmic visual acuity chart. And his left eyeball movement dysfunction and eyeball outward protruding get a partially relief. Lessons: EAF occurring in the orbit is a very rare disease and immunohistochemical results of EAF can be IgG4 negative.


Introduction
Eosinophilic Angiocentric Fibrosis (EAF) is considered to be a kind of benign IgG4-related disease diagnosed mainly relying on results of histology. [1]The first known case reported most like EAF was a case of intranasal occurrence granuloma faciale published in 1983 by Douglas K. Holmes et al. [2] In that case, the patient complained of right-sided nasal obstruction, whose right-sided intranasal mass' gross pathologic report described the tissue as gray-tan.Microscopic examination showed a perivascular infiltrate of eosinophils and histiocytes involving the small arteries and capillaries.And they diagnosed this case as granuloma faciale. [2]Two years after Douglas K. Holmes report, P.F.Roberts [3] reported 3 patients who had developed an obstructive lesion in the upper airways.The 3 patients showed a remarkably similar histological appearance: there were eosinophils cluster around and migrated through the vessel wall, showed degranulation and were accompanied by a variable number of plasma cells and lymphocytes in the peri-vascular space.The more mature foci show early fibrosis characterized by proliferation of spindleshaped fibroblasts producing a pseudogranulomatous appearance. [3]P.F.Roberts named the lesion as EAF.Besides, P.F.Roberts paper noted that the presence of a striking infiltrate of eosinophils suggests that allergy to an inhaled agent may play a part in the etiology of the disease.And this view is persuasive in the light of papers and current data: there appears to be a higher incidence of allergic and atopic disorders consisting of asthma, drug allergy, environmental allergy, urticaria and allergic rhinitis in patients with EAF than in the general population. [4]And a summary of EAF case reports had been presented showed that the most common anatomic site involved was the nose (77.8%), and the most common manifestation was nasal obstruction (66.7%).Many research even described EAF as a very rare neoplasm of the sinonasal tract and the upper respiratory system. [5]So our case of EAF is very rare for the lesion involving the orbits and the patient of our case complained not for nasal obstruction but for the right eye visual deterioration.This atypical growth site and symptoms Informed consent was obtained from the patient for publication of this case report details, and written informed consent was secured from the legal guardian of kin for this patient.

The authors have no funding and conflicts of interest to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.can easily lead to misdiagnosis.We have also made some innovations in the treatment of this patient on the common surgical approach, which we hope can be helpful in the treatment of this disease thereafter.These are the rarity of our case and the value of reporting it.

Patient information
A 68-year-old man from a rural area of Inner Mongolia Autonomous Region presented to their local hospital for a 2-month history of vision loss.And his orbital computer tomography showed that there was a lesion in his left orbit.Then he went to our hospital for further diagnosis and treatment.
This patient has a history of gastric polyps that were surgically treated 2 years ago, but he could not offer more details.The patient had a drinking history of 30 years with an average of 150 grams per day.

Clinical findings
The physical examination of the patient revealed that the patient left eye was protruding outward with incomplete opening and closing of the eyelid (Fig. 1).And his left eyeball movement had difficulties in all directions, left eye vision was 0.4 tested in the standard logarithmic visual acuity chart.
On magnetic resonance imaging (MRI) plain and enhanced scanning, there was a mass of equal T1 and slightly long T2 signals in the fat space behind the left eyeball, the lateral side of the left eyeball, and the muscle space below the left eyeball.And there was obvious homogeneous enhancement on enhancement scanning, and the size of enhancement signals was about 5.1*2.8*2.5 cm, and the lesion cannot be clearly demarcated from the optic nerve, posterior globe of the left eyeball, and the posterolateral wall of the left eyeball.The left external and inferior rectus muscles and lacrimal gland could not be clearly identified on the MRI because of the invasion of the tumor.Part of the tumor broke through the lateral orbital wall outwardly to the left temporal fossa, invaded the left temporal muscle, and grew toward the orbital apex, invaded the left cavernous sinus, and the left optic chiasm could be seen to be widened on the nuclear magnetic image, and the lesion protruded backward and downward into the pterygopalatine fossa through the left infraorbital fissure, with a slight thickening and enhancement of the meninges in front of the temporal pole.The meninges are slightly thickened and are intensified during the enhancement phase (Figs.2-7).

Therapeutic intervention
Since there were no contraindications, we performed surgery under general anesthesia for him after preoperative preparation.
What we want to introduce is our surgery methods.We used the fronto orbitozygomatic approach to remove the superior orbital wall and the zygomatic arch, found that the entire temporal fossa and the muscles in the infratemporal fossa had been invaded by the lesion and were present as hard-textured (Fig. 17).The tumor occupied the space below and temporal side of the eye, causing the eye ball shifted to the superior and nasal side of the orbit.The tumor also protruding into the infratemporal fossa and invading the bone of the orbital wall.Besides, we noticed that the texture of the tumor was tough with a poor blood supply (Fig. 17).We carefully separated the tumor from normal tissue and resected the tumor in piecemeal resection and the tumor was eventually removed completely (Fig. 18).Postoperative treatment with methylprednisolone.

Follow-up and outcomes
After surgery, the left eye vision of this patient was 0.6 tested in the standard logarithmic visual acuity chart.His left eyeball abduction movements gained a significant improvement, but his left eyeball movement in all directions still worse than normal people and eyeball outward protruding get partially relief (still being a little protruding) (Fig. 19).Here are MRI plain and enhanced scanning after the surgery 5 days (Figs.20-23).And postoperative pathology revealed that it is a rare case of IgG4negative orbital EAF.We followed up him for 2 years after he  discharged from our hospital, and there were no signs of the tumors' recurrence (the patient did not have complaints that deterioration of vision or recurrence of eyeball obvious protruding, but he also did not want to go to hospital to do more times of review for economic reason.

Discussion
Orbital EAF various clinical manifestations include diffuse inflammatory lesions or localized mass lesions, and it is also invasive, spreading easily to surrounding tissues and often causing bone damage.Besides, the symptoms that EAF exhibits are strongly tied to the anatomical site, which is mostly the nose, sinuses, and subglottic region.As a result, the primary symptoms were growing nasal blockage and stuffiness, breathing difficulty, epistaxis, and discomfort.These vague symptoms are the primary cause of the normally protracted delay in diagnosis of this disease. [6,7]So the signs and symptoms of Orbital EAF are also probably more related to compression.And here we give some examples from the literature reported by other scholars: Igal Leibovitch case report presented the patient with a 6-week history of right periorbital edema and painless proptosis, with a 3-mm right nonaxial proptosis and 2 mm lateral globe displacement was noted. [8]One another article put out that proptosis is less likely to happen in the orbital EAF patient, [9] but eyeball proptosis in our case was significant.We have summarized the signs and symptoms of reported orbital EAF in Table 1.
The imaging of EAF also is nonspecific and untypically either in computer tomography or MRI, and usually it shows a well-circumscribed submucosal soft tissue density mass. [6]For example, soft tissue thickening of the septum and lateral nasal walls, as well as clouding or opacification of the sinuses, are common imaging findings in EAF. [6]Igal Leibovitch, 1 case report author of Orbital EAF, described their case MRI showed the mass was mainly orbital, with no obvious nasal involvement. [8]Another case of orbital EAF case MRI, a contrast-enhanced coronal scan shows a thick rind of mildly enhancing soft tissue around right eyeball and soft tissue thickening seen isointense to the muscle, around right eyeball. [10]Magnetic imaging of our EAF case showed isosignal with the muscle, and was significantly enhanced by contrast.
The characteristic histologic feature of EAF are as follows: a dense fibrotic stroma with a perivascular "onion skin-like" whorling pattern and a dense inflammatory infiltrate that the major cells are eosinophils, consisting of lymphocytes, plasma cells, and some neutrophils. [11]Microscopic pathology in our case showed proliferative fibrous tissue, eosinophils, lymphocytes and plasma cells.And they distributed in concentric circles around the vessel.On the basis of these typical histological characteristics, we were able to diagnose the patient as an orbital EAF.
However, our case IgG4 showed in immunohistochemical result is negative.But the definition of EAF usually descripted as a kind of rare, benign IgG4-related disease (IgG4-RD) diagnosed by histology, [1] which require that IgG4+/IgG plasma cell ratio >40% and more than 10 IgG4 + plasma cells per high-power field. [1]There are no pathologists who have studied and explained why some patients are negative for IgG4, which is an interesting and worthwhile question.We also summarized the immunohistochemical results of reported orbital EAF in Table 2.
Differential diagnoses including granuloma faciale, Wegener granulomatosis, Churg-Strauss syndrome, and Kimura disease are discussed by many other papers, [12] so we would not discuss EAF differential diagnoses in this article.
Surgical resection could be the first choice of treatment, while there are recurrent cases of EAF after surgery, [13][14][15][16] and a firsttime incomplete surgical resection or even a biopsy may contribute to the development of the tumor in a negative way. [17]esides, there are scholars view that systemic and topical corticosteroids as ineffective. [18]But in any way, it is hard to diagnosis EAF without pathological results, and glucocorticoids appear to be effective initially. [19]Therefore, combined surgery to remove as much of the lesion as possible with glucocorticoid or other medicines like azathioprine, mycophenolate mofetil, and methotrexate as remission-maintenance drugs may be the best option at present.
We summarize the surgical experience of this patient: firstly, adequate exposure of the lesion according to preoperative MRI can ensure maximal tumor resection.Using the fronto orbitozygomatic approach to open the cranium, and then use the grinding drill to grind all the bones of the middle skull base and the lateral wall of the cavernous sinus, at the same time, cut the falciform ligament, and cut the dura at the proximal fissure for about half a centimeter, and then adjust the focus to the carotid artery pool along this area using a microscope, releasing the cerebrospinal fluid to make the brain tissues to collapse, so that the tumor can be exposed sufficiently at the level of the middle skull base, and then resected the tumor according to a certain sequence.The sequence was medio-lateral orbital, infraorbital wall, and after removing the intraorbital tumor then turning to the infratemporal fossa.Secondly, according to the texture of tumor to choose cavitron ultrasonic surgical aspirator, monopolar knives scissors and sharp knives.Thirdly localized bone with abnormal hyperplasia is considered to be invasive and can be removed by grinding drill.Fourthly, the anatomical structure should be strictly mastered, especially  the neurovascular which has been mutated and displaced.We hope that our experience will inform our peers in the surgical removal of similar tumors.
On the end of our article, we also want to point out the limitations of this research.First, this case lacks laboratory tests for serum IgG4.Based on published literature, the diagnosis of IgG4-RD relies on the basis of clinical, radiological (localized or diffuse hypertrophy of one or more organs classically involved in the course of IgG4-RD), laboratory (serum IgG4 greater than or equal to 135 mg/dL) and immunohistochemical criteria (intense polyclonal round cell infiltration and fibrosis, IgG4 + plasma cell infiltration: IgG4+/IgG plasma cell ratio >40% and more than 10 IgG4 + plasma cells per high-power field). [1]Since this patient was not sure that what kind of disease was preoperatively, taking a serum IgG4 test was not thought of before operation.We hope that our colleagues who read this article will learn from our lesson that in patients with orbital occupations of unknown cause, to perform a serum IgG4 test could be helpful for clues to diagnose the disease.Secondly, although the article mentions a 2-year follow-up showing no signs of recurrence, more detailed follow-up data, such as long-term changes in patients' vision recovery, are lacking.Because follow-up is constrained by various factors including the patient financial reasons, and as far as the follow-up results of this patient are concerned, the treatment for this patient (especially the operation method) achieved a satisfactory therapeutic outcome.Besides, we look forward to the academic community having operation method comparisons for this kind of type orbital disease in the future.

a
Department of Neurosurgery, The Second Hospital of Jilin University, Changchun, China, b Department of Neurosurgery, Chian-Japan Union Hospital of Jilin University, Changchun, China, c Department of Pathology, Chian-Japan Union Hospital of Jilin University, Changchun, China.

Figure 1 .
Figure 1.The patient had a protruding left eyeball with severe limitation of motion in all directions.

Figure 2 .
Figure 2. The patient MRI coronal T1 phase left posterior ocular fat space, left lateral ocular, and left inferior ocular muscular space masses are isosignal (red arrows).MRI = magnetic resonance imaging.

Figure 3 .
Figure 3.The patient MRI coronal T2 phase left posterior ocular fat space, left lateral ocular, and left infraocular muscular space masses showed slightly high signal (red arrows).MRI = magnetic resonance imaging.

Figure 4 .
Figure 4. Patient MRI cross-sectional T1 phase with isosignal nonsignificant enhancement of the left posterior fat space, left lateral eye, and left inferior muscle space masses (red arrows).MRI = magnetic resonance imaging.

Figure 5 .
Figure 5.The patient MRI cross-sectional T2 phase showed slightly high signal without significant enhancement of the left posterior fat space, left lateral eyeball, and left inferior muscle space masses (red arrows).MRI = magnetic resonance imaging.

Figure 6 .
Figure 6.Patient MRI sagittal T1 phase with isosignal (red arrows) in the left posterior fat space, left lateral eye, and left inferior muscle space mass.MRI = magnetic resonance imaging.

Figure 7 .
Figure 7.The patient MRI sagittal T2 phase showed slightly high signal (red arrows) in the left posterior fat space, left lateral eyeball, and left inferior muscle space mass.MRI = magnetic resonance imaging.

Figure 17 .
Figure 17.This is an intraoperative photo, shows the tumor (yellow arrow) and the left side of the eye ball (red arrow).

Figure 19 .
Figure 19.Postoperatively, the patient left ocular motility dysfunction and outward protrusion of the eyeball were partially relieved.

Table 1
Summarizing EAF cases of orbital origination or orbital involvement described in the literature. 2 mo: ocular motility almost returned to normal, the anterior pole of the right eye was normal and chemosis and proptosis in the left had significantly improved, the left eye showed no improvement; the Marcus Gunn pupil and anisocoria persisted in the left eye EAF = eosinophilic angiocentric fibrosis.